Diabetes Drugs: DPP-4 Inhibitors

DPP-4 inhibitors, a relatively new class of drugs for Type 2 diabetes, were introduced in 2006. Sitagliptin (brand name Januvia), the first medicine in this class, was approved for the treatment of Type 2 diabetes in October 2006; in July 2009, a second DPP-4 inhibitor, saxagliptin (Onglyza), was approved. These drugs are approved for use as additional therapy in people with Type 2 diabetes alone or in combination with metformin (brand name Glucophage and others), sulfonylureas (Diabinese, DiaBeta, Glynase, Micronase, Glucotrol, Glucotrol XL, Amaryl), and thiazolidinediones (Actos, Avandia).

This very recent addition of a new class of drugs might seem like the result of the latest research, but in fact, the science behind DPP-4 inhibitors goes back to research started in the early 1900’s. As I mentioned in my post on GLP-1 agonists, the hormone glucagon-like peptide-1, or GLP-1, has a profound effect on both stimulating the release of insulin from the pancreas and delaying stomach emptying. Unfortunately, it is active only for a very short time because it is broken down by an enzyme called dipeptidyl peptidase-4, or DPP-4. Blocking DPP-4 prolongs the effect of GLP-1, and hence enhances insulin secretion and the slowed emptying of the stomach.

It is known that people with Type 2 diabetes have impaired GLP-1 secretion and elevated DPP-4 activity, so blocking DPP-4 could directly address some of the issues in people with diabetes. Since DPP-4 inhibitors enhance the body’s own ability to release insulin, they can only be used in the treatment of Type 2 diabetes. Of note, researchers have found that after certain types of gastrointestinal surgery to treat obesity, GLP-1 levels increase and glucose control improves, suggesting that enhanced GLP-1 activity may be partially responsible for helping with blood glucose management in people who have had this surgery.

As the first DPP-4 inhibitor approved, there is more data available for sitagliptin than for saxagliptin. The recommended initial dose of sitagliptin is 100 milligrams once a day, but for people with kidney disease, lower doses are recommended. Research indicates that this medicine causes a reduction in HbA1c (an indicator of blood glucose control over the previous 2–3 months) of approximately 0.7%. (By comparison, metformin reduces HbA1c by roughly 1.1%.) In combination, a dose of 50 milligrams of sitagliptin and 1,000 milligrams of metformin produces an HbA1c reduction of roughly 1.9%.

A major study evaluated sitagliptin in people who had not achieved adequate blood glucose control with metformin alone. The study showed no real differences in HbA1c reductions produced by a combination of sitagliptin and metformin compared to a combination of glipizide (Glucotrol) and metformin. However, those on the sitagliptin treatment had a significantly lower incidence of hypoglycemia (low blood glucose) compared to those on the glipizide treatment. Additionally, there was an average weight loss of roughly three pounds among people taking sitagliptin, while people taking glipizide gained approximately two pounds, on average.

The recommended dose of saxagliptin is 2.5 milligrams or 5 milligrams; for people with moderate or severe kidney impairment, 2.5 milligrams is recommended. The removal of saxagliptin from the body can be slowed by the use of certain drugs such as the antifungal ketoconazole (Nizoral and others). For people taking these drugs, the dose of saxagliptin should be limited to 2.5 milligrams.

When used by itself, saxagliptin results in HbA1c reductions between 0.4% and 0.5%. When added to metformin, the HbA1c reductions are approximately 0.7%, with similar results being produced by the combination of saxagliptin and a thiazolidinedione (pioglitazone [Actos] or rosiglitazone [Avandia]) or glipizide.

Side effects seen with the use of sitagliptin include inflammation of the nasal passages and throat, upper respiratory tract infections, and headache. By itself, sitagliptin poses a low risk for causing low blood glucose; this risk is significantly increased when a sulfonylurea is taken in combination with sitagliptin. The U.S. Food and Drug Administration recently released information indicating that there may be a connection between sitagliptin and pancreatitis (a serious inflammation of the pancreas that usually requires hospitalization), based on reports of this condition occurring in 88 people using sitagliptin in the roughly three years since its approval.

Side effects of saxagliptin include upper respiratory tract infection, urinary tract infection, and headache, but not at rates much greater than those seen with placebo (inactive treatment). Although this medicine poses a low risk of hypoglycemia when used by itself, the risk is slightly increased when saxagliptin is used along with a sulfonylurea.

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